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Viruses
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Virology and Immunology of Gene Therapy
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Virology and Immunology of Gene Therapy

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: 28 February 2025 | Viewed by 5090

Special Issue Editors

Prof. Dr. Weidong Xiao

E-Mail Website
Guest Editor
Herman B Wells Center for Pediatric Research, Indiana University, Indianapolis, IN 46202, USA
Interests: gene therapy; AAV; tissue tropism; vector; hemophilia
Prof. Dr. Jianming Qiu

E-Mail Website
Guest Editor
Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, KS 66160, USA
Interests: parvovirus; DNA replication; mRNA processing; antiviral; virus receptor; gene therapy

Special Issue Information

Dear Colleagues,

The interplay between virology, immunology, and gene therapy is a dynamic and critical area of research. Virology provides the tools and vectors for gene therapy and immunology and ensures that these tools are safely and effectively accepted by the body, and gene therapy offers new ways to treat diseases by harnessing and modifying biological systems. Therefore, we have created a Special Issue to address the most important scientific areas of the field:

  • Development of efficient viral vectors;
  • Development of new vector production technology to reduce potential immune responses;
  • Better vector characterization technology;
  • Immunogenicity of viral vectors;
  • Immunotherapy using gene therapy;
  • Overcoming pre-existing immunity;
  • Gene editing for immune modulation;
  • Autoimmune diseases and gene therapy;
  • Viral vector-based vaccines.

Prof. Dr. Weidong Xiao
Prof. Dr. Jianming Qiu
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Viruses is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • gene therapy
  • viral vector
  • vaccine
  • immune responses
  • viruses
  • AAV
  • lentiviral vectors
  • neutralizing antibody

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Further information on MDPI's Special Issue polices can be found here.

Published Papers (4 papers)

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Research

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11 pages, 2015 KiB  
Article
The Adeno-Associated Virus Replication Protein Rep78 Contains a Strictly C-Terminal Sequence Motif Conserved Across Dependoparvoviruses
by David G. Karlin
Viruses 2024, 16(11), 1760; https://doi.org/10.3390/v16111760 - 12 Nov 2024
Viewed by 464
Abstract
Adeno-Associated Viruses (AAVs, genus Dependoparvovirus) are the leading gene therapy vector. Until recently, efforts to enhance their capacity for gene delivery had focused on their capsids. However, efforts are increasingly shifting towards improving the viral replication protein, Rep78. We discovered that Rep78 [...] Read more.
Adeno-Associated Viruses (AAVs, genus Dependoparvovirus) are the leading gene therapy vector. Until recently, efforts to enhance their capacity for gene delivery had focused on their capsids. However, efforts are increasingly shifting towards improving the viral replication protein, Rep78. We discovered that Rep78 and its shorter isoform Rep52 contain a strictly C-terminal sequence motif, DDx3EQ, conserved in most dependoparvoviruses. The motif is highly negatively charged and devoid of prolines. Its wide conservation suggests that it is required for the life cycle of dependoparvoviruses. Despite its short length, the motif’s strictly C-terminal position has the potential to endow it with a high recognition specificity. A candidate target of the DDx3EQ motif might be the DNA-binding interface of the origin-binding domain of Rep78, which is highly positively charged. Published studies suggest that this motif is not required for recombinant AAV production, but that substitutions within it might improve production. Full article
(This article belongs to the Special Issue Virology and Immunology of Gene Therapy)
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20 pages, 4613 KiB  
Article
Redundancy in Innate Immune Pathways That Promote CD8+ T-Cell Responses in AAV1 Muscle Gene Transfer
by Ning Li, Sandeep R. P. Kumar, Di Cao, Maite Munoz-Melero, Sreevani Arisa, Bridget A. Brian, Calista M. Greenwood, Kentaro Yamada, Dongsheng Duan and Roland W. Herzog
Viruses 2024, 16(10), 1507; https://doi.org/10.3390/v16101507 - 24 Sep 2024
Viewed by 1355
Abstract
While adeno-associated viral (AAV) vectors are successfully used in a variety of in vivo gene therapy applications, they continue to be hampered by the immune system. Here, we sought to identify innate and cytokine signaling pathways that promote CD8+ T-cell responses against [...] Read more.
While adeno-associated viral (AAV) vectors are successfully used in a variety of in vivo gene therapy applications, they continue to be hampered by the immune system. Here, we sought to identify innate and cytokine signaling pathways that promote CD8+ T-cell responses against the transgene product upon AAV1 vector administration to murine skeletal muscle. Eliminating just one of several pathways (including DNA sensing via TLR9, IL-1 receptor signaling, and possibly endosomal sensing of double-stranded RNA) substantially reduced the CD8+ T-cell response at lower vector doses but was surprisingly ineffective at higher doses. Using genetic, antibody-mediated, and vector engineering approaches, we show that blockade of at least two innate pathways is required to achieve an effect at higher vector doses. Concurrent blockade of IL-1R1 > MyD88 and TLR9 > MyD88 > type I IFN > IFNaR pathways was often but not always synergistic and had limited utility in preventing antibody formation against the transgene product. Further, even low-frequency CD8+ T-cell responses could eliminate transgene expression, even in MyD88- or IL-1R1-deficient animals that received a low vector dose. However, we provide evidence that CpG depletion of vector genomes and including TLR9 inhibitory sequences can synergize. When this construct was combined with the use of a muscle-specific promoter, transgene expression in muscle was sustained with minimal local or systemic CD8+ T-cell response. Thus, innate immune avoidance/blockade strategies by themselves, albeit helpful, may not be sufficient to prevent destructive cellular responses in muscle gene transfer because of the redundancy of immune-activating pathways. Full article
(This article belongs to the Special Issue Virology and Immunology of Gene Therapy)
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16 pages, 2615 KiB  
Article
Viral Vector Based Immunotherapy for Peanut Allergy
by Miguel Gonzalez-Visiedo, Roland W. Herzog, Maite Munoz-Melero, Sophia A. Blessinger, Joan M. Cook-Mills, Henry Daniell and David M. Markusic
Viruses 2024, 16(7), 1125; https://doi.org/10.3390/v16071125 - 13 Jul 2024
Viewed by 1545
Abstract
Food allergy (FA) is estimated to impact up to 10% of the population and is a growing health concern. FA results from a failure in the mucosal immune system to establish or maintain immunological tolerance to innocuous dietary antigens, IgE production, and the [...] Read more.
Food allergy (FA) is estimated to impact up to 10% of the population and is a growing health concern. FA results from a failure in the mucosal immune system to establish or maintain immunological tolerance to innocuous dietary antigens, IgE production, and the release of histamine and other mediators upon exposure to a food allergen. Of the different FAs, peanut allergy has the highest incidence of severe allergic responses, including systemic anaphylaxis. Despite the recent FDA approval of peanut oral immunotherapy and other investigational immunotherapies, a loss of protection following cessation of therapy can occur, suggesting that these therapies do not address the underlying immune response driving FA. Our lab has shown that liver-directed gene therapy with an adeno-associated virus (AAV) vector induces transgene product-specific regulatory T cells (Tregs), eradicates pre-existing pathogenic antibodies, and protects against anaphylaxis in several models, including ovalbumin induced FA. In an epicutaneous peanut allergy mouse model, the hepatic AAV co-expression of four peanut antigens Ara h1, Ara h2, Ara h3, and Ara h6 together or the single expression of Ara h3 prevented the development of a peanut allergy. Since FA patients show a reduction in Treg numbers and/or function, we believe our approach may address this unmet need. Full article
(This article belongs to the Special Issue Virology and Immunology of Gene Therapy)
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Review

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16 pages, 2862 KiB  
Review
The Expression and Function of the Small Nonstructural Proteins of Adeno-Associated Viruses (AAVs)
by Cagla Aksu Kuz, Shane McFarlin and Jianming Qiu
Viruses 2024, 16(8), 1215; https://doi.org/10.3390/v16081215 - 29 Jul 2024
Cited by 1 | Viewed by 1132
Abstract
Adeno-associated viruses (AAVs) are small, non-enveloped viruses that package a single-stranded (ss)DNA genome of 4.7 kilobases (kb) within their T = 1 icosahedral capsid. AAVs are replication-deficient viruses that require a helper virus to complete their life cycle. Recombinant (r)AAVs have been utilized [...] Read more.
Adeno-associated viruses (AAVs) are small, non-enveloped viruses that package a single-stranded (ss)DNA genome of 4.7 kilobases (kb) within their T = 1 icosahedral capsid. AAVs are replication-deficient viruses that require a helper virus to complete their life cycle. Recombinant (r)AAVs have been utilized as gene delivery vectors for decades in gene therapy applications. So far, six rAAV-based gene medicines have been approved by the US FDA. The 4.7 kb ssDNA genome of AAV encodes nine proteins, including three viral structural/capsid proteins, VP1, VP2, and VP3; four large nonstructural proteins (replication-related proteins), Rep78/68 and Rep52/40; and two small nonstructural proteins. The two nonstructured proteins are viral accessory proteins, namely the assembly associated protein (AAP) and membrane-associated accessory protein (MAAP). Although the accessory proteins are conserved within AAV serotypes, their functions are largely obscure. In this review, we focus on the expression strategy and functional properties of the small nonstructural proteins of AAVs. Full article
(This article belongs to the Special Issue Virology and Immunology of Gene Therapy)
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